Tsujimoto Shin-Ichi, Yanagimachi Masakatsu, Tanoshima Reo, Urayama Kevin Y, Tanaka Fumiko, Aida Noriko, Goto Hiroaki, Ito Shuichi
Department of Pediatrics, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama City, Japan.
Center for Clinical Epidemiology, St. Luke's International University, Chuo-ku, Tokyo, Japan.
Pediatr Blood Cancer. 2016 Nov;63(11):1983-9. doi: 10.1002/pbc.26090. Epub 2016 Jul 11.
Methotrexate (MTX) can lead to neurotoxicity and asymptomatic leukoencephalopathy. However, the mechanism of MTX-related leukoencephalopathy is obscure. MTX and its metabolites inhibit 5-aminoimidazole-4-carboxamide ribonucleotide formiltransferase (ATIC) and promote adenosine release. Recently, it has been reported that adenosine and its receptor are related to certain central nervous system diseases. We investigated whether adenosine pathway gene polymorphisms and clinical factors were related to MTX-related leukoencephalopathy in pediatric patients affected by hematological malignancies.
Fifty-six Japanese childhood acute lymphoblastic leukemia or lymphoma patients were investigated. Patients were evaluated by magnetic resonance imaging of the brain before maintenance therapy or stem cell transplantation. Gene polymorphisms within the adenosine pathway (ATIC, adenosine A2A receptor [ADORA2A]) and the MTX pathway (methylenetetrahydrofolate reductase [MTHFR] and ABCB1) were genotyped using TaqMan assays. Clinical data were collected by accessing the medical records. MTX-related leukoencephalopathy was evaluated by a pediatric neurologist.
Twenty-one (37%) of 56 patients developed MTX-related leukoencephalopathy. Four of 21 patients developed clinical neurotoxicity. The minor allele CC genotype of rs2298383 (ADORA2A) was associated with MTX-related leukoencephalopathy (P = 0.010, odds ratio = 5.81, 95% confidence interval 1.50-22.50). High cumulative dose of systemic MTX was associated with MTX-related leukoencephalopathy after adjusting for sex, ADORA2A polymorphism, and prolonged high MTX concentration (P = 0.042, odds ratio = 1.18, 95% confidence interval 1.01-1.37).
ADORA2A rs2298383 and high cumulative dose of systemic MTX administration were significantly associated with MTX-related leukoencephalopathy. Our results indicate that pharmacological intervention within the adenosine pathway may be both a treatment and preventative option for MTX-related leukoencephalopathy.
甲氨蝶呤（MTX）可导致神经毒性和无症状性白质脑病。然而，MTX相关性白质脑病的机制尚不清楚。MTX及其代谢产物可抑制5-氨基咪唑-4-甲酰胺核糖核苷酸甲酰转移酶（ATIC）并促进腺苷释放。最近，有报道称腺苷及其受体与某些中枢神经系统疾病有关。我们调查了腺苷途径基因多态性和临床因素是否与血液系统恶性肿瘤患儿的MTX相关性白质脑病有关。
对56例日本儿童急性淋巴细胞白血病或淋巴瘤患者进行了研究。在维持治疗或干细胞移植前，通过脑部磁共振成像对患者进行评估。使用TaqMan分析对腺苷途径（ATIC、腺苷A2A受体[ADORA2A]）和MTX途径（亚甲基四氢叶酸还原酶[MTHFR]和ABCB1）内的基因多态性进行基因分型。通过查阅病历收集临床数据。由儿科神经科医生评估MTX相关性白质脑病。
56例患者中有21例（37%）发生了MTX相关性白质脑病。21例患者中有4例出现临床神经毒性。rs2298383（ADORA2A）的次要等位基因CC基因型与MTX相关性白质脑病相关（P = 0.010，比值比 = 5.81，95%置信区间1.50 - 22.50）。在调整性别、ADORA2A多态性和MTX高浓度持续时间后，全身MTX的高累积剂量与MTX相关性白质脑病相关（P = 0.042），比值比 = 1.18，95%置信区间1.01 - 1.37）。
ADORA2A rs2298383和全身MTX的高累积剂量与MTX相关性白质脑病显著相关。我们的结果表明，腺苷途径内的药物干预可能是MTX相关性白质脑病的治疗和预防选择。
